核多聚腺嘌呤结合蛋白PABPN1的积聚和募集作用及分子机制

Poly(A) binding protein nuclear 1 (PABPN1) is an RNA-binding protein locating in the nuclei of mammalian cells. Expansion of Ala-rich region in the N terminus of PABPN1 is proposed to cause misfolding and amyloid aggregation that may lead to a disease of oculopharyngeal muscular dystrophy. In this project, we will investigate the biochemical properties of PABPN1 and their structural bases, including RNA-binding, amyloid aggregation and sequestration of RNA-binding proteins. We will realize (1) whether the Ala-rich sequence is the amyloidogenic core of PABPN1 aggregation; (2) how the RRM domain recognizes RNA sequences; and (3) how the PABPN1 aggregates sequester RNA-binding proteins. By study of the protein in molecular and cellular levels, we will understand the relationship between PABPN1 aggregation and the cell toxicity or degeneration. The research will provide fundamental information for further deciphering pathologies of the degenerative diseases caused by PABPN1 and other RNA-binding proteins.

核多聚腺嘌呤结合蛋白 (PABPN1) 是存在于哺乳动物细胞核内的RNA结合蛋白，其N-端的丙氨酸序列延伸突变可能造成该蛋白质发生错误折叠并形成淀粉样积聚，导致遗传性眼咽部肌肉萎缩症。本申请项目拟研究PABPN1蛋白的生化特性、结构基础、RNA结合、积聚以及募集RNA结合蛋白的机制。我们将阐明(1) PABPN1中的N-端丙氨酸丰富序列是否为积聚核心; (2) RRM结构域与RNA的识别作用，(3) PABPN1积聚物对其它RNA结合蛋白的募集作用。通过研究蛋白质分子在细胞中的行为深入认识PABPN1的积聚与细胞毒性或退行性的关系。该研究成果将为进一步理解PABPN1及其它RNA结合蛋白的致病机制提供依据。

核多聚腺嘌呤结合蛋白 (PABPN1) 是哺乳动物细胞核内的RNA-结合蛋白，其N-端的丙氨酸序列延伸突变和RNA结合能力被认为是造成该蛋白质发生液-固相变和淀粉样积聚的原因。本项目应用生物化学和细胞生物学的技术方法研究了丙氨酸序列延伸和RNA结合对PABPN1的相变和积聚的影响及其机制。项目揭示了PABPN1的丙氨酸延伸改变其液-液相分离性质并促使细胞中PABPN1的核颗粒(Speckles)向积聚包涵体(Aggregates or Inclusions)的相变过程，阐明了RNA(特别是mRNA)在PABPN1的相分离和相变中的作用。同时，我们还研究了PABPN1的积聚对其它RNA-结合蛋白的募集作用和功能损伤。通过该项目的实施，研究成果为进一步理解PABPN1的蛋白质病理以及相关的遗传性眼咽部肌肉萎缩症的发病机制提供依据。

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